Abstract Systemic characterized production treatment which lupus erythematosus (SLE) is a chronic, potentially fatal autoimmune disease by abnormal activation of autoreactive T and B cells resulting in the of autoantibodies that cause widespread tissue and organ damage. Current strategies rely heavily corticosteroids and immunosuppressive agents, are limited by suboptimal efficacy and by a significant burden of morbidity. , on Identification of alternative, safer and more comprehensive approaches targeting different elements of disease pathogenesis need to be explored. Our new published and preliminary data support the provocative and intriguing concept that erythropoietin (EPO), a hormone produced predominantly by the kidney in adults, plays an unanticipated role in controlling autoimmune response in lupus and improving clinical outcomes. Expanding beyond EPO's established role in erythrocyte development, our new data demonstrate that EPO a) improves disease severity in murine models of lupus, b) inhibits mouse and human Th17, T follicular helper cells (TFH), and Th1, while it increases T follicular regulatory cells (Tfr), c) induces and stabilizes Treg, and d) inhibits germinal center B cell formation and autoantibody production. We have identified molecular mechanisms that link EPO to some of these effects and show that they apply to humans given clinically used doses of EPO. EPO therapy, at doses used to correct anemia, augments frequencies of circulating CD4+CD25+CD127lo Treg in human subjects. Altogether, our findings support the following hypothesis to be tested in this project: EPO directly inhibits autoreactive Th17 and TFH, and simultaneously induces and maintains Treg and Tfr, together reducing disease severity in lupus. We will test this hypothesis by determining the effects of exogenous and kidney-derived EPO on murine lupus (aim 1), deciphering the mechanisms through which EPO selectively inhibits Th17 and TFH (aim 2), while EPO promotes Treg/Tfr induction and stability (aim 3). The proposed work will define the role of EPO as a mediator of self- tolerance and will delineate cellular and molecular mechanisms underlying EPO's effects on Th17, TFH, and Treg/Tfr. In addition to deciphering mechanisms, the studies will provide preclinical data on the utility of EPO as a therapeutic agent for improving disease activity in animals, findings that could potentially be translated to SLE patients.